The invention relates to oral, multiple unit formulations of delayed-release pellets which contain a pharmacologically active component coated by at least one pharmaceutically acceptable, release-delaying substance, and to a process for their preparation.
Single unit controlled release tablet dosage forms of drugs have known disadvantages compared to the more desirable multiple unit dosage forms. In single dosage matrix tablets the active ingredient is dispersed as a solid in an inert, release delaying matrix. The embedding matrixing material that slows the release of the drug is usually an insoluble plastic (e.g. methyl acrylate-methacrylate, polyvinyl chloride, or polyethylene), a hydrophilic polymer (e.g. methylcellulose, hydroxypropylmethylcellulose, or sodium carboxyl methylcellulose), or fatty compounds (e.g. various waxes, such as carnauba wax, or glyceryl stearate). Such tablets pass undisintegrated through the gastrointestinal tract, and become ever smaller due to breakdown (erosion tablets), or wherein the active compound is released only in the intestine (enteric-coated tablets), in either case depleting the surface inward through the matrix by dissolution or diffusion through the matrix to the external solution.
Multiple unit dosage forms are usually contained within a rapid dissolving capsule, or are compressed into a tablet, and soon after ingestion upon its dissolution fall apart into the multiple units, such as pellets. The sub-units or pellets have the desired slow release properties of the dosage form. In contrast to the matrixed formulations, the multiple unit pellets are each surrounded by a polymeric delay release film coating that provides the controlled, slowed release of the active ingredient from within the pellet. These coated dosage forms are generally referred to as xe2x80x9creservoir devicesxe2x80x9d when diffusion phenomena occur through the release slowing coat, or xe2x80x9cencapsulated formulationsxe2x80x9d when the slow release coat slowly dissolves (see e.g. Remington""s Pharmaceutical Sciences, Mack Publ. Co.). In the case of the single unit, matrixed delayed-release dosage forms, considerable variations can occur in the gastric residence times, and this can lead to an irregular passage through the gastrointestinal tract and thus to differing, fluctuating blood level values. Local irritation is also becomes of lesser concern also being reduced by the use of multiple unit pharmaceutical dosage forms. xe2x80x9cDose dumpingxe2x80x9d or the too rapid release of the active compound from delayed-release dosage forms (see e.g. H. Blume, xe2x80x9cBiopharmazeutische Aspekte von Multiple Unit Dosage Forms; ein Vergleich mit Single Unitsxe2x80x9d [Biopharmaceutical aspects of multiple unit dosage forms; a comparison with single units], published by Capsugel, Basel, and delivered at a symposium in November 1988 in Hamburg).
A variety of pharmaceutical formulations having delayed-release coatings are described, for example, in EP No. 147,780, in the form of tablets and granules which contain an active compound core and are coated with a film of polyvinyl alcohol.
In EP No. 634,366 an oral dosage form for delayed release tramadol preparations is disclosed wherein the active compound is either embedded in a delayed-release matrix of hydrophilic or hydrophobic polymers, long-chain fatty acids or fatty alcohols and one or more polyalkylene glycol. Film-coated spheroids are also described in which the active ingredient is embedded in a xe2x80x9cspheronizingxe2x80x9d material, such as in microcrystalline cellulose, and coated with a release controlling film.
In EP No. 731,694 (WO95/14460) delayed-release opioid formulations, for example pellets, are described which provide an analgesic effect over at least 24 hours after oral administration. The pellets have of an active ingredient-containing core which is covered with a polymer film suitable for delaying the release of the active. In addition to the polymers the film contains an acid-soluble compound and a plasticizer. The use of plasticizers, however, can be most disadvantageous, because these migrate out of the membrane, and this composition change can affect the release of active compound during storage. EP No. 147 780 describes on page 2 that a chemical interaction between plasticizer and the active compound can also take place and this leads to a reduction in the shelf life of the product.
It is mentioned in Sucker, Fuchs, Speiser xe2x80x9cPharmazeutische Technologiexe2x80x9d Thieme Verlag Publisher. Stuttgart, 1978, that beside its actual film-improving property, the plasticizer affects water vapor permeability and the disintegration. The admittedly low but noticeable vapor pressure furthermore leads to an evaporation of the plasticizer, resulting in an alteration of the physical properties, such as the dissolution rate of the film.
Pellet formulations are distinguished by their large surface area because of the presence of many, often a few hundred sub-units per therapeutic dose. In the case of readily soluble substances such as tramadol hydrochloride, this can lead to a need for delayed release material, which undesirably reduces the active ingredient content of the pellet formulation. This is particularly undesirable in the case of actives which are administered at relatively high doses, because the quantity of pellets necessitates the use of a larger hard gelatine capsule. This is therapeutically undesirable, because it can be unpleasant for the patient.
The present invention is a multiple unit oral pharmaceutical dosage form having a plurality of pellets in a water soluble capsule or in a tablet compressed from the pellets, wherein each pellet contains (a) a substantially inert core, (b) an active ingredient layer over the inert core, and containing (i) a pharmacologically active particulate ingredient, (ii) a nonembedding amount of a binder for adhering the active ingredient over the inert core, and optionally (iii) a pharmaceutically acceptable, inert adjuvant, such as colloidal silica, and (c) a coating over the active ingredient layer for retarding the release of the active ingredient from the active ingredient layer into an aqueous body fluid solvent in situ. Suitably the nonembedding amount of the binder is from about 1% wt. to about 10% wt. based on the active ingredient layer. Suitably the binder in the active ingredient layer is a mixture of ethylcellulose and shellac, suitably in a weight proportion of from about 1:9, to from about 9:1. The coating for retarding the release suitably contains from about 70% wt. to about 95% wt. based on the coating, of a substantially water-insoluble, pharmacologically inert, particulate material, and a binder. Suitably the pharmacologically inert, particulate material is talcum, and the binder in the active ingredient layer is suitably identical to the binder in the coating.
As used throughout the specification and the claims, the term xe2x80x9cactivexe2x80x9d and xe2x80x9cactive ingredientxe2x80x9d means any pharmacologically active material that is suitable for use in reservoir type or in encapsulated type, i.e. nonmatrixed dosage forms. Thus the choice of the active employed in the dosage form of the present invention is a noncritical feature, wherein the active can suitably be an antiinflammatory, such as aspirin, diclofenac, ibuprofen, acetaminophen, indomethacin, ketoprofen, and hydrocortisone; an antiemetic, such as metoclopramide, and domperidon; an antihypertensive, such as clonidine, captopril, atenolol and propranolol; an opioid analgesic such as codeine, dihydrocodeine, hydrocodone, hydromorphone, morphine, oxycodone, fenantyl, tramadol, tilidin, and tilidin-naloxone combination; a nonopioid analgesic, such as paracetamol, aspirin, ibuprofen, acetaminophen, dipyrone, ketoprofen, naproxene, and flupirtine; an antiasthmatic, such as theophylline, and azelastine; an antiepileptic, such as carbamazepine, and phenytoin; and an H2 antagonist, such as ranitidine, and cimetidine; and pharmaceutically acceptable salts and esters of the above. Most suitably the active ingredient is tramadol or a pharmaceutically acceptable salt or ester thereof.
As used throughout the specification and the claims, reference to a nonembedding amount of binder means that the vast majority of the active ingredient layer is the active ingredient itself, and only so little binder is present that the active ingredient is not embedded in any embedding material or matrix of any kind, but under a microscope it visibly retains its particulate identity. The active ingredient layer is applied over the inert core by spraying it, or a solution thereof, onto the core, together with a small amount of the binder in a solution. It can be seen under a microscope that the binder solution does not coat or embed the active ingredient particles, but they visibly retain their particulate integrity. It has been found that the amount of binder in solution that will not fully wet the particles of the active ingredient, but will still permit their bonding to the inert core and to each other, is suitably between from about 1% wt. to about 10% wt. based on the active ingredient layer. The optimum concentration of the binder will generally depend within that range on such factors as the identities of the solvent of the binder, the method of spraying the solution on the active, any solvent for the active and its evaporation rate upon the application of the active, and the particle size and surface characteristics, such as specific solvent wettability of the active ingredient and any other particulate adjuvant that may be used therewith. All of these variables can be routinely tested and optimized by persons having average skill in the pharmaceutical formulation art.
Any reference throughout the specification and the claims to water solubility of any material in the dosage form of the present invention, and to release of the active ingredient into a solvent medium, include solubility within the aqueous biological solvent in the body of a patient at the site or sites at which the dosage form is to release its active ingredient content.